KR20080049780A - Indol-3-yl-carbonyl-azaspiro derivatives as vasopressin receptor antagonists - Google Patents

Abstract

This invention relates to indol-3-yl-carbonyl-azaspiro derivatives which act as Via receptor antagonists and which are represented by Formula (I) wherein the azaspiro-head group A and the residues R1, R2 and R3 are as defined herein. The invention further relates to pharmaceutical compositions containing such compounds, their use in medicaments against dysmenorrhea, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, obsessive compulsive disorder, anxiety and depressive disorders, and methods of preparation thereof.

Description

INDOL-3-YL-CARBONYL-AZASPIRO DERIVATIVES AS VASOPRESSIN RECEPTOR ANTAGONISTS as a vasopressin receptor antagonist

The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof:

Where

R ¹ is H; C _{1 -6} - alkyl; Aryl, 5- or 6-membered heteroaryl or sulfonylaryl, each optionally substituted by one or more B; ^{_{- (CH 2) m -R a}} ( where R ^a is CN, OR ^i, NR ⁱ R ^ii, each of which is optionally substituted by one or more B C _{3 -6} - cycloalkyl, 4 to 7 heterocycle won Roalkyl, aryl, or 5 or 6 membered heteroaryl); _{- (CH 2) n - (} CO) -R b or _{- (CH 2) n - (} SO 2) -R b ( where R ^b is C _{1 -6} - alkyl, C _{1 -6} - alkoxy, C _{3 -6} -cycloalkyl,-(CH ₂ ) _m -NR ⁱⁱⁱ R ^iv ,

NR ⁱ R ^ii, respectively, it is optionally substituted by one or more B A C _{3 -6} - a cycloalkyl, 4 to 7 membered heterocycloalkyl of, aryl, or 5 or 6 membered heteroaryl), or; or

R ¹ and R ³ together with the indole ring to which they are attached form a 5 or 6 membered heterocycloalkyl optionally substituted by = O;

At least one R ² is present, wherein each R ² is the same or different,

R ² is H; OH; Halo; CN; Nitro; -NR ⁱⁱⁱ R ^iv, optionally substituted C _{1 -6} by -alkyl; C _{1 -6} - alkoxy; -O-CH ₂ -C _{2 -6} - alkenyl, or one or more benzyloxy, or; Or two R ² together with the indole ring to which they are attached form an oxo or dioxo bridge;

R ³ is H; Halo; - (CO) -R ^c (where R ^c is C _{1 -6} - _{alkyl, - (CH 2) n -NR} i R ii, - (CH 2) n -NR iii R iv, or C _{1 -6} - 5 or 6 membered heterocycloalkyl optionally substituted by alkyl); or

Each is _{halo, -O (CO) -C 1 -6} - alkyl or -NH (CO) R ^d (where R ^d is from optionally substituted C _{1 -6} by a halo or nitro-alkyl, or R ^d are each halo, nitro, C _{1 -6} -alkyl or C _{1 -6-alkyl} optionally substituted by halo-aryl or 5 or 6 membered heteroaryl), optionally substituted by a C _{1 -6-alkyl,} or Aryl;

B is halo; CN; NR i R ii ; CN, halo or C 1 -6 - alkoxy optionally substituted by C 1 -6 - alkyl; C 1-6 -alkoxy; C 1 -6 - haloalkoxy; C 3 -6 - cycloalkyl; -C (O) OC 1 -6 - alkyl; -C (O) NR i R ii ; -C (O) -C 1-6 -alkyl; -S (O) 2 -C 1 -6 - alkyl; -S (O) 2 -NR i R ii ; Or (CR iii R iv ) n -phenyl, or (CR iii R iv ) n -5 or 6 membered heteroaryl, wherein the phenyl or 5 or 6 membered heteroaryl moiety is halo, CN, NR i R ii , CN or C 1 -6 - an alkoxy optionally substituted by C 1 -6 - alkyl, C 1-6 - alkoxy, C 1 -6 - haloalkoxy, C 3 -6 - cycloalkyl, -C (O) OC 1 -6-alkyl, -C (O) -NR i R ii, -C (O) -C 1-6 - alkyl, -S (O) 2 -C 1-6 -alkyl, and -S (O) 2 -NR i R ii optionally substituted by one or more substituent (s) selected from the group consisting of;

R ⁱ and R ⁱⁱ are each independently H, C _{1 -6} - alkyl, C _{1 -6} - alkyl, ^{-NR iii R iv, - (CO} ) OC 1 -6 - ^{alkyl, -C (O) NR iii R} iv _{, -C (O) -C 1 -6} - _{alkyl, -S (O) 2 -C 1} -6 - alkyl, or ^{_{-S (O) 2 -NR iii R}} iv , and;

R ⁱⁱⁱ and R ^iv are each independently H or C _{1 -6} - alkyl;

m is 1 to 6;

n is 0 to 4;

A is a group of formula a or b:

(Wherein

R ⁴ is H or C _{1 -6} - alkyl;

R ⁵ is aryl optionally substituted by halo).

The compound of formula (I) may contain some asymmetric carbon atoms. Accordingly, the present invention encompasses all stereoisomeric forms of the compounds of formula (I), including each individual enantiomer and mixtures thereof.

The compounds of formula (I) have been found to have good activity on the Vla receptor. Accordingly, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of dysmenorrhea, hypertension, chronic heart failure, inappropriate secretion of vasopressin, cirrhosis, kidney syndrome, obsessive compulsive disorder, anxiety and depressive disorder. Serves the purpose.

Vasopressin is a 9 amino acid peptide mainly produced by the periventricular nucleus of the hypothalamus. Three vasopressin receptors, all belonging to Group I G protein coupled receptors, are known. The V1a receptor is expressed in the brain, liver, vascular smooth muscle, lungs, uterus and testes, the V1b or V3 receptor is expressed in the brain and pituitary gland, the V2 receptor is expressed in the kidneys to regulate water discharge and anti-diuretic effect of vasopressin Mediate.

In the peripheral, vasopressin acts as a neurohormone and stimulates vasoconstriction, glycogenolysis and antidiuresis. In the brain, vasopressin acts as a neuromodulator and rises in the amygdala during stress (Ebner, K., CT Wotjak, et al. (2002). “Forced swimming is a tonsil to regulate stress-mimicking strategies in rats. Triggers vasopressin release in the body. ”Eur J Neurosci 15 (2): 384-8]. The V1a receptor is widely expressed in the brain and especially in the cerebral limbic region (which plays an important role in the control of anxiety), such as tonsils, lateral septum and hippocampus. Indeed, V1 knockout mice show a decrease in anxiety behavior in the plus-maze, open field and contrast boxes (Bielsky, IF, SB Hu, et al. (2003). "Severe social cognitive impairment in vasopressin V1a receptor knockout mice. And reduction of behaviors such as anxiety. "Neuropsychopharmacology]). Downregulation of the V1a receptor using antisense oligonucleotide injection in the septum also results in a decrease in anxiety behavior (Landgraf, R., R. Gerstberger, et al. (1995). "V1 vasopressin receptor antisense oligodeoxy in the septum). Nucleotides reduce vasopressin binding, social discrimination, and anxiety related behavior in rats. "Regul Pept 59 (2): 229-39].

The V1a receptor also mediates cardiovascular effects of vasopressin in the brain by centrally regulating blood pressure and heart rate in the nucleus in isolation (Michelini, LC and M. Morris (1999). “Endogenous vasopressin is a cardiovascular system for exercise. Control the response. "Ann NY Acad Sci 897: 198-211]. In the periphery, this induces vascular smooth muscle contraction and chronic inhibition of the V1a receptor improves hemodynamic parameters in myocardial infarction rats (Van Kerckhoven, R., I. Lankhuizen, et al. (2002). " Chronic vasopressin V (1A) (but not V (2)) receptor antagonism prevents heart failure in chronically infarcted rats. "Eur J Pharmacol 449 (1-2): 135-41).

Therefore, vasopressin receptor antagonist is useful as a therapeutic agent for diseases of dysmenorrhea, hypertension, chronic heart failure, inappropriate secretion of vasopressin, cirrhosis, kidney syndrome, obsessive compulsive disorder, anxiety and depressive disorder.

Preferred indications for the present invention are the treatment of anxiety and depressive disorders.

As used herein, the term "aryl" means a monovalent cyclic aromatic hydrocarbon moiety consisting of a mono-, bi- or tricyclic aromatic ring. Examples of aryl moieties include, but are not limited to, optionally substituted phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenyl In addition to sulfidyl, diphenylsulfonyl, and diphenylisopropylidedenyl, there are those specifically exemplified by the following examples of the present invention. Substituents for aryl include but are not limited to halogen, C _{1 -6-alkoxy} include - alkyl and C _{1 -6.} Preferred aryls are phenyl and naphthyl, even more preferably phenyl. The aryl moiety of the present invention also forms together with the carbons of the aryl moiety a condensed, saturated or partially saturated 5- to 6-membered ring containing one or two heteroatoms selected from O and N. Ortho-substituted by two substituents. Preferably said additional ring is a 5- to 6-membered ring containing two oxygen atoms. Examples of such substituted aryl moieties include, but are not limited to, benzodioxanyl, dihydro-benzofuranyl, benzodioxolyl, benzopyranyl, benzoxazinyl, benzoxazinonyl, benzopiperidinyl, benzopipera Genyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, as well as those specifically illustrated by the following embodiments of the present invention.

"C _{1 -6-alkyl"} refers to a saturated straight chain of 1 to 6 carbon atoms - or branched-chain hydrocarbon group, such as methyl, ethyl, propyl, isopropyl, n- butyl, i- butyl, 2-butyl, t-butyl etc. are shown. Preferred C _{1 -6} - alkyl group is C _{1 -4} - groups with the group, that having 1 to 4 carbon atoms.

"C _{1 -6} - alkoxy" is the term alkyl moiety is as defined above, represents a group which is attached via an oxygen atom. Preferred C _{1 -6} - alkoxy groups are those specifically illustrated by the embodiments of the present invention to not only the methoxy and ethoxy.

"C _{2 -6} - alkenyl" term represents a carbon chain having 2 to 6 carbon atoms containing a double bond in its chain. C _{2 -6} - alkenyl groups include ethenyl, propen-1-yl, propen-2-yl, buten-1-yl, butene-3-yl, penten-1-yl, penten-2-yl, Penten-3-yl, penten-4-yl, hexen-1-yl, hexen-2-yl, hexen-3-yl, hexen-4-yl, and hexen-5-yl as well as examples of the present invention Are specifically exemplified by them.

The term "benzyloxy" refers to a benzyl group bonded through an oxygen atom.

The term "halogen" or "halo" refers to chlorine (Cl), iodine (I), fluorine (F) and bromine (Br).

"C _{1 -6-haloalkyl"} refers to C _{1 -6} as defined above which is substituted by one or more halogen-represents an alkyl. C _{1 -6} - Examples of haloalkyl are methyl, ethyl and substituted by one or more Cl, F, Br or I atom (s) are not limited to, propyl, isopropyl, butyl, sec-butyl, tert- Butyl, pentyl or n-hexyl as well as those specifically exemplified by the following examples of the present invention. Preferred C _{1 -6-haloalkyl} are difluoro- or trifluoro-methyl or ethyl.

"C _{1 -6-haloalkoxy"} is C _{1 -6} as defined above which is substituted by one or more halogen-represents an alkoxy group. C _{1 -6} - An example of a haloalkoxy group is specifically illustrated by one or more Cl, F, as well as to a methoxy or ethoxy substituted with a Br or I atom (s) to embodiments of the present invention are not limited to There are things. Preferred C _{1 -6-haloalkoxy} are difluoro- or trifluoro-methoxy or ethoxy.

"C _{3 -6} - cycloalkyl" term represents a cyclic monovalent or divalent saturated carbonyl moiety consisting of a monocyclic ring. Cycloalkyl is 1, 2, 3, or can be optionally substituted with four substituents, wherein each substituent here is as independent as otherwise specifically does not represent hydroxy, C _{1 -6} - alkyl, C _{1 -6} - alkoxy, Halogen, amino. Examples of cycloalkyl moieties include optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl and optionally substituted cyclohexyl as well as those specifically exemplified by the embodiments of the present invention.

The term “4-7 membered heterocycloalkyl” refers to a ring member, which comprises one, two or three heteroatoms selected from nitrogen, oxygen, and sulfur and the remainder being one ring of 4 to 7 atoms that are carbon atoms. Means a monovalent saturated moiety made up. 4 to be the 7-heterocycloalkyl agent optionally substituted with 1, 2, 3 or 4 substituents, and one each of the substituents herein, unless otherwise specifically indicated, independently hydroxy, C _{1 -6} - alkyl, C _{1 -6} - alkoxy, C _{1 -6} - thioalkyl, halo, C _{1 -6} - haloalkyl, C _{1 -6} - hydroxyalkyl, alkoxycarbonyl, amino, C _{1 -6} - alkylamino, di ( C _1-6 ) alkylamino, aminocarbonyl, or carbonylamino. Examples of heterocyclic moieties include, but are not limited to, optionally substituted oxetane, optionally substituted tetrahydro-furanyl, optionally substituted piperidinyl, optionally substituted pyrrolidinyl, optionally substituted morpholinyl, optionally substituted blood Ferrazinyl and the like or those specifically exemplified in the present invention. Substituent is C _{1 -6} - alkyl, C _{1 -6} - alkoxy, C _{1 -6} - haloalkyl, halo, CN, OH, NH ₂ may be selected from those specifically illustrated by the embodiments of the subsequent examples, as well as have.

The term "5 or 6 membered heteroaryl" refers to a ring member which is an aromatic ring of 5 or 6 ring atoms containing 1, 2 or 3 ring heteroatoms selected from N, O and S and the remainder being carbon atoms it means. 5 or 6 membered heteroaryl may be optionally substituted with one, two, three or four substituents, wherein each substituent which here does not represent a different specifically, independently hydroxy, C _{1 -6} - alkyl, C _1-6 - alkoxy, C _{1 -6-thioalkyl,} halo, C _1-6 - haloalkyl, C _{1-6-hydroxyalkyl,} alkoxycarbonyl, amino, C _1-6 - alkylamino, di (C _1-6 ) alkylamino, aminocarbonyl, or carbonylamino. Examples of heteroaryl moieties include, but are not limited to, optionally substituted imidazolyl, optionally substituted oxazolyl, optionally substituted thiazolyl, optionally substituted pyrazinyl, optionally substituted pyrrolyl, optionally substituted pyrazinyl, optionally substituted pyri Diyl, optionally substituted pyrimidinyl, optionally substituted furanyl, and those specifically exemplified in the present invention.

The term "sulfonylaryl" refers to an aryl group as defined above bound through a sulfonyl group.

The expression “two R ² together with the indole ring to which they are attached form an oxo or dioxo bridge” binds to two adjacent carbon atoms of the phenyl or indole ring of the compound of formula I to which one of R ² is bonded Represents an oxo or dioxo bridge of the formula

Examples of groups exemplifying the expression “R ¹ and R ³ together with the indole ring to which they are attached form a 5 or 6 membered heterocycloalkyl optionally substituted by ═O” are as follows:

The term "pharmaceutically acceptable acid addition salts" refers to inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, salts with p-toluenesulfonic acid, as well as those specifically exemplified by the examples of the present invention.

In detail, the present invention relates to compounds of formula (I) as well as to pharmaceutically acceptable salts thereof:

Formula I

Where

R ¹ is either H, C _{1 -6} - alkyl or, respectively, or a heteroaryl or aryl sulfonyl aryl, 5 or 6 membered optionally substituted by one or more _{B, - (CH 2) m} -R a ( where in R ^a is CN, oR ^i, NR ⁱ R ^ii, each of which is optionally substituted by one or more B C _{3 -6} - cycloalkyl, 4 to 7 membered-heterocycloalkyl, aryl, or 5 or 6 membered heteroaryl is aryl), or _{- (CH 2) n - (} CO) -R b or _{- (CH 2) n - (} SO 2) -R b ( where R ^b is C _{1 -6} - alkyl, C _{1 - 6} -alkoxy, C _{3 -6-cycloalkyl,} - (CH _{2) m} -NR ⁱⁱⁱ R ^iv, NR ⁱ R ^ii, each substituted with a C _3-6 optionally substituted by one or more B-cycloalkyl, 4 to 7 Is a heterocycloalkyl, aryl, or a 5 or 6 membered heteroaryl), or R ¹ and R ³ together with the indole ring to which they are attached are 5 or 6 membered heterocycloalkyl optionally substituted by = O To form;

R ² is H, OH, halo, CN, by a nitro, -NR ⁱⁱⁱ R ^iv, optionally substituted C _{1 -6} - alkyl, C _1-6 - _{alkoxy, -O-CH 2 -C 2 -6} - Al At least one of kenyl, and benzyloxy, or two R ² together with the indole ring to which they are attached form an oxo or dioxo bridge;

R ³ is either H, halo or, - (CO) -R ^c (where R ^c is C _{1 -6} - _{alkyl, - (CH 2) n -NR} i R ii, - (CH 2) n -NR iii R ^iv, or C _{1 -6} - a by alkyl, 5 or 6 membered heterocycloalkyl optionally substituted), or _{halo, -O (CO) -C 1 -6} - alkyl, or -NH (CO) R ^d (where R ^d is an optionally substituted C _{1 -6} by a halo or nitro-alkyl, or R ^d is halo, nitro, C _1-6 - alkyl, C _{1 -6-alkyl} optionally substituted by halo aryl or 5 or 6 membered heteroaryl), optionally substituted by a C _{1 -6-alkyl} or aryl;

B is halo, CN, NR i R ii, CN, halo or C 1 -6 - an alkoxy optionally substituted by C 1 -6 - alkyl, C 1-6 - alkoxy, C 1 -6 - haloalkoxy, C 3 6 - cycloalkyl, -C (O) OC 1 -6-alkyl, -C (O) NR i R ii, -C (O) -C 1-6 - alkyl, -S (O) 2 -C 1 -6 -alkyl, -S (O) 2 -NR i R ii , (CR iii R iv ) n -phenyl, or (CR iii R iv ) n -5 or 6 membered heteroaryl, wherein phenyl or 5 Or a 6 membered heteroaryl residue is

^{Halo, CN, NR i R ii,} CN or C _{1 -6} - an alkoxy optionally substituted by C _{1 -6} - alkyl, C _{1 -6} - alkoxy, C _{1 -6} - haloalkoxy, C _{3 -6} - cyclopenten _{alkyl, -C (O) OC 1 -6} - ^{alkyl, -C (O) -NR i R} ii, -C (O) -C 1-6 - _{alkyl, -S (O) 2 -C 1} -6 - Optionally substituted by one or more substituent (s) selected from the group consisting of alkyl and -S (O) ₂ -NR ⁱ R ⁱⁱ );

R ⁱ and R ⁱⁱ are H, C _{1 -6} - alkyl, C _{1 -6} - alkyl, ^{-NR iii R iv, - (CO} ) OC 1 -6 - ^{alkyl, -C (O) -NR iii R} iv, - C (O) -C _1-6 - _{alkyl, -S (O) 2 -C 1} -6 - alkyl, or ^{_{-S (O) 2 -NR iii R}} iv , and;

R ⁱⁱⁱ and R ^iv are H or C _{1 -6} - alkyl;

m is 1 to 6;

n is 0 to 4;

A is a group of formula a or b:

Formula a

Formula b

(Wherein

R ⁴ is H or C _{1 -6} - alkyl;

R ⁵ is aryl optionally substituted by halo).

Further embodiments of the invention include compounds wherein A is group (b) and R ¹ = R ² = R ³ = H; And A is a group (b) and R ² = OH, C _{1 -6} in the 5-position of the indole-alkoxy or benzyloxy compound of the formula The compound or a pharmaceutically acceptable of the (I) as taught in the present invention are excluded, Possible salts are included.

Further embodiments of the invention include compounds wherein A is group (b) and R ¹ = R ² = R ³ = H; And A is a group (b) and R ² = OH, C _{1 -6} in the 5-position of the _{indole-alkoxy, -O-CH 2 -C 2 -6} - alkenyl, or benzyloxy which compounds are excluded, the present invention Or a pharmaceutically acceptable salt thereof.

A further embodiment of the invention includes a compound of formula (I) or a pharmaceutically acceptable salt thereof as disclosed herein, excluding compounds wherein R ¹ = R ² = R ³ = H.

Compounds of formula (Ia) in accordance with the invention are also included in compounds of formula (I):

Where

R ¹ to R ⁵ are as defined above for Formula (I).

Preferred compounds of formula (Ia)

R ¹ is H; C _{1 -6} - alkyl; Aryl, 5- or 6-membered heteroaryl or sulfonylaryl, each optionally substituted by one or more B; ^{_{- (CH 2) m -R a}} ( where R ^a is CN, NR ⁱ R ^ii, each of which is optionally substituted by one or more C _{3 -6} B - cycloalkyl, 4 to 7 membered heterocycloalkyl of aryl Or 5 or 6 membered heteroaryl; _{- (CH 2) n - (} CO) -R b or _{- (CH 2) n - (} SO 2) -R b ( where R ^b is C _{1 -6} - or more alkoxy, NR ⁱ R ^ii, each one 4 to 7 membered heterocycloalkyl, aryl, or 5 or 6 membered heteroaryl optionally substituted by B); Or R ¹ and R ³ together with the indole ring to which they are attached form a 5 or 6 membered heterocycloalkyl optionally substituted by = O;

At least one R ² is present, wherein each R ² is the same or different,

R ² is H; OH; Halo; -NR ⁱⁱⁱ R ^iv, optionally substituted C _{1 -6} by -alkyl; Or C _{1 -6} - represents at least one alkoxy group;

R ³ is H; - (CO) -R ^c (where R ^c is ^{_{- (CH 2) n -NR i}} R ii, - (CH 2) n -NR iii R iv, C 1 -6 - alkyl optionally substituted by a 5 or 6 membered heterocycloalkyl); Or each of which is optionally substituted by a halo-C _{1 -6} - alkyl or aryl;

B is halo; NH ₂ ; CN or a C _{1 -6-alkoxy} optionally substituted by C _{1 -6} -alkyl; C _{1 -6} - alkoxy; C _{1 -6} - haloalkoxy; C _{3 -6} - cycloalkyl; -C (O) OC _{1 -6} - alkyl; - (CR ⁱⁱⁱ R ^iv) _n -, and phenyl (wherein phenyl is halo, by CN or halo, optionally substituted C _{1 -6} - alkyl and C _{1 -6} - substituent at least one selected from the group consisting of alkoxy group (s) Optionally substituted);

R ⁱ and R ⁱⁱ are each independently H, C _{1 -6} - alkyl, C _{1 -6} - alkyl, ^{-NR iii R iv, - (CO} ) OC 1 -6 - alkyl, -C (O) -NR ⁱⁱⁱ R _{^{iv, -C (O) -C 1}} -6 - _{alkyl, -S (O) 2 -C 1} -6 - alkyl, or ^{_{-S (O) 2 -NR iii R}} iv , and;

R ⁱⁱⁱ and R ^iv are each independently H or C _{1 -6} - alkyl;

m is 1 to 6;

n is 0 to 4;

R ⁴ is H or C _{1 -6} - alkyl;

R ⁵ is aryl optionally substituted by halo, or a pharmaceutically acceptable salt thereof.

Most preferred compounds of formula (Ia)

R ¹ is H; C _{1 -6} - alkyl; Phenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, sulfonylphenyl, each optionally substituted by one or more B; ^{_{- (CH 2) m -R a}} ( where R ^a is CN, NR ⁱ R ^ii, each of which is optionally substituted by one or more B C _{3 -6} - cycloalkyl, oxetanyl, piperazinyl, tetrahydro Pyranyl, morpholinyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, pyrazolyl or imidazolyl); _{- (CH 2) n - (} CO) -R b or _{- (CH 2) n - (} SO 2) -R b ( where R ^b is C _{1 -6} - or more alkoxy, NR ⁱ R ^ii, each one Oxetanyl, piperidinyl, piperazinyl, morpholinyl or phenyl optionally substituted by B); Or R ¹ and R ³ together with the indole ring to which they are attached form a 5 or 6 membered heterocycloalkyl which may be substituted by (CO);

At least one R ² is present, wherein each R ² is the same or different,

R ² is H, OH, Cl, Br, -NR iii R iv on optionally substituted by C _{1 -6-alkyl,} OMe, or OEt, and one or more of;

R ³ is H; - (CO) -R ^c (where R ^c is ^{_{- (CH 2) n -NR i}} R ii, - (CH 2) n -NR iii R iv, respectively, are C _{1 -6} - alkyl optionally substituted by a Oxetanyl, piperidinyl, piperazinyl or morpholinyl); Each of the Cl by an optionally substituted C _{1 -6} - alkyl or aryl;

B is halo; NH ₂ ; CN or a C _{1 -6-alkoxy} optionally substituted by C _{1 -6} -alkyl; C _{1 -6} - alkoxy; C _{1 -6} - haloalkoxy; C _{3 -6} - cycloalkyl; -C (O) OC _1-6 -alkyl, or - (CR ⁱⁱⁱ R ^iv) _n-phenyl (wherein phenyl is halo, optionally substituted by CN or halo, C _1-6 -alkyl and C _1-6 - Optionally substituted by one or more substituent (s) selected from the group consisting of alkoxy);

R ⁱ and R ⁱⁱ are each independently H, C _{1 -6} - alkyl, C _{1 -6} - alkyl, ^{-NR iii R iv, - (CO} ) OC 1 -6 - alkyl, -C (O) -NR ⁱⁱⁱ R _{^{iv, -C (O) -C 1}} -6 - _{alkyl, -S (O) 2 -C 1} -6 - alkyl, or ^{_{-S (O) 2 -NR iii R}} iv , and;

R ⁱⁱⁱ and R ^iv are each independently H or C _{1 -6} - alkyl;

m is 1 to 6;

n is 0 to 4;

R ⁴ is H or C _{1 -6} - alkyl;

R ⁵ is aryl optionally substituted by halo, or a pharmaceutically acceptable salt thereof.

Further preferred compounds according to the invention are

R ¹ is H; C _{1 -6} - alkyl; Phenyl optionally substituted by one or more B; -(CH ₂ ) _m -R ^a , wherein R ^a is NR ⁱ R ⁱⁱ ; -(CH ₂ ) _n- (CO) -R ^b , wherein R ^b is NR ⁱ R ⁱⁱ ;

At least one R ² is present, wherein each R ² is the same or different,

R ² is _{H, Cl, Br, C 1} -6 - one or more alkyl and;

R ³ is H; -(CO) -R ^c , wherein R ^c is-(CH ₂ ) _n -NR ⁱ R ⁱⁱ ,-(CH ₂ ) _n -NR ⁱⁱⁱ R ^iv ); By Cl, optionally substituted C _{1 -6} - alkyl;

B is halo,

Alkyl -NR ⁱⁱⁱ R ^iv, - R ⁱ and R ⁱⁱ are each independently H, C _{1 -6} - alkyl, C _{1 -6}

R ⁱⁱⁱ and R ^iv are each independently H or C _{1 -6} - alkyl;

m is 1 to 6;

n is 0 to 4;

R ⁴ is H or C _{1 -6} - alkyl;

Or a pharmaceutically acceptable salt thereof, wherein R ⁵ is aryl optionally substituted by halo.

A compound of formula (Ia) according to any one of the embodiments as described above, wherein R ² is one or two halogen atom (s) and R ¹ , R ³ , R ⁴ and R ⁵ are disclosed herein; This is more preferable.

Preference is furthermore given to compounds of the formula (la) according to any one of the embodiments described above, wherein R ² is a halogen atom at the 6 position of indole. Preferably, the halogen atom at position 6 of the indole is Cl.

In one R ² is 5 times of the indole position C _{1 - 6} alkyl or a halogen atom, one of R ² is a halogen atom at the 6-position of the indole of formula according to any one of the embodiments as described above Ia The compound of is more preferable. Preferably, R ² at position 5 of the indole is F or Me, and R ² at position 6 of the indole is Cl.

R ³ is C _{1 -6} - the compound of formula Ia according to any one of the alkyl, the above-described embodiment is more preferable.

R ³ is C _{1 -6} - is alkyl, and R ² is H the compounds of formula Ia according to any one of the embodiments as described above is more preferable.

R ³ is C _{1 -6} - alkyl and R ² is H or R ³ is H and R ² is the formula according to any one of the halogen, particularly Cl in the 6-position of the indole, embodiments as described above Ia The compound of is more preferable.

The following compounds are included in the present invention:

2- [6-Chloro-3- (3-methyl-4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] decane-8-carbonyl) -indol-1-yl]- N, N-dimethyl-acetamide;

8- [6-Chloro-1- (3,5-difluoro-benzyl) -1H-indole-3-carbonyl] -3-methyl-1-phenyl-1,3,8-triaza-spiro [ 4.5] decan-4-one;

2- [6-Chloro-3- (3-methyl-4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] decane-8-carbonyl) -indol-1-yl]- N-methyl-acetamide;

8- (1-benzyl-6-chloro-1H-indole-3-carbonyl) -3-methyl-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one;

8- [6-Chloro-1- (3-chloro-2-fluoro-benzyl) -1H-indole-3-carbonyl] -3-methyl-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one;

8- [6-chloro-1- (2-dimethylamino-ethyl) -1H-indole-3-carbonyl] -3-methyl-1-phenyl-1,3,8-triaza-spiro [4.5] Decan-4-one;

2- [6-Chloro-3- (3-methyl-4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] decane-8-carbonyl) -indol-1-yl]- N- (2-dimethylamino-ethyl) -acetamide;

8- (1-benzyl-2-methyl-1H-indol-3-carbonyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one;

8-[(1-benzyl-2-methyl-1H-indol-3-yl) carbonyl] -3-methyl-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one ;

8- (6-chloro-1H-indol-3-carbonyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one;

2- [6-Chloro-3- (3-methyl-4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] decane-8-carbonyl) -indol-1-yl]- Acetamide;

8- (1-benzyl-2-methyl-1H-indole-3-carbonyl) -1- (4-chloro-phenyl) -1,3,8-triaza-spiro [4.5] decan-4-one;

8- (1H-indole-3-carbonyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one; And

8-[(6-chloro-1H-indol-3-yl) carbonyl] -3-methyl-1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one.

Compounds of formula (Ib) according to the invention are also included in compounds of formula (I):

Where

R ¹ to R ³ are as defined above for Formula (I).

Preferred compounds of formula Ib are

R ¹ is H; C _{1 -6} - alkyl; Aryl, 5- or 6-membered heteroaryl or sulfonylaryl, each optionally substituted by one or more B; ^{_{- (CH 2) m -R a}} ( where R ^a is CN, NR ⁱ R ^ii, each of which is optionally substituted by one or more C _{3 -6} B - cycloalkyl, 4 to 7 membered heterocycloalkyl of aryl Or 5 or 6 membered heteroaryl; _{- (CH 2) n - (} CO) -R b or _{- (CH 2) n - (} SO 2) -R b ( where R ^b is C _{1 -6} - or more alkoxy, NR ⁱ R ^ii, each one 4 to 7 membered heterocycloalkyl optionally substituted by B); Or R ¹ and R ³ together with the indole ring to which they are attached form a 5 or 6 membered heterocycloalkyl optionally substituted by = O;

At least one R ² is present, wherein each R ² is the same or different,

R ² is H, halo, -NR ⁱⁱⁱ R ^iv on optionally substituted by C _{1 -6-alkyl,} and one or more;

R ³ is H; - (CO) -R ^c (where R ^c is ^{_{- (CH 2) n -NR i}} R ii, - (CH 2) n -NR iii R iv, C 1 -6 - alkyl optionally substituted by a 5 or 6 membered heterocycloalkyl); Or each of which is optionally substituted by a halo-C _{1 -6} - alkyl or aryl;

B is halo; NH ₂ ; CN or a C _{1 -6-alkoxy} optionally substituted by C _{1 -6} -alkyl; C _{1 -6} - alkoxy; C _{1 -6} - haloalkoxy; C _{3 -6} - cycloalkyl; -C (O) OC _{1 -6} - alkyl; Or _{^{- (CR iii R iv) n}} - , and phenyl (wherein phenyl is halo, by CN or halo, optionally substituted C _{1 -6} - alkyl and C _{1 -6} - substituent at least one selected from the group consisting of alkoxy (the Optionally substituted);

R ⁱ and R ⁱⁱ are each independently H, C _{1 -6} - alkyl, C _{1 -6} - alkyl, ^{-NR iii R iv, - (CO} ) OC 1 -6 - alkyl, -C (O) -NR ⁱⁱⁱ R _{^{iv, -C (O) -C 1}} -6 - _{alkyl, -S (O) 2 -C 1} -6 - alkyl, or ^{_{-S (O) 2 -NR iii R}} iv , and;

R ⁱⁱⁱ and R ^iv are each independently H or C _{1 -6} - alkyl;

m is 1 to 6;

n is 0-4, or a pharmaceutically acceptable salt thereof.

Most preferred compounds of formula Ib are

R ¹ is H; C _{1 -6} - alkyl; Phenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, or sulfonylphenyl, each of which is optionally substituted by one or more B; ^{_{- (CH 2) m -R a}} ( where R ^a is CN, NR ⁱ R ^ii, each of which is optionally substituted by one or more B C _{3 -6} - cycloalkyl, oxetanyl, piperazinyl, tetrahydro Pyranyl, morpholinyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, pyrazolyl or imidazolyl); _{- (CH 2) n - (} CO) -R b or _{- (CH 2) n - (} SO 2) -R b ( where R ^b is C _{1 -6} - or more alkoxy, NR ⁱ R ^ii, each one Oxetanyl, piperidinyl, piperazinyl, morpholinyl or phenyl optionally substituted by B); Or R ¹ and R ³ together with the indole ring to which they are attached form a 5 or 6 membered heterocycloalkyl optionally substituted by = O;

At least one R ² is present, wherein each R ² is the same or different,

R ² is ^{H, Cl, Br, -NR iii} R iv on optionally substituted by C _{1 -6-alkyl,} and one or more;

R ³ is H; - (CO) -R ^c (where R ^c is ^{_{- (CH 2) n -NR i}} R ii, - (CH 2) n -NR iii R iv, respectively, are C _{1 -6} - alkyl optionally substituted by a Oxetanyl, piperidinyl, piperazinyl, morpholinyl); Each of the Cl by an optionally substituted C _{1 -6} - alkyl or aryl;

B is halo; NH ₂ ; CN or a C _{1 -6-alkoxy} optionally substituted by C _{1 -6} -alkyl; C _{1 -6} - Al koksi; C _{1 -6} - haloalkoxy; C _{3 -6} - cycloalkyl; -C (O) OC _{1 -6} - alkyl; Or _{^{- (CR iii R iv) n}} - , and phenyl (wherein phenyl is halo, by CN or halo, optionally substituted C _{1 -6} - alkyl and C _{1 -6} - substituent at least one selected from the group consisting of alkoxy (the Optionally substituted);

R ⁱ and R ⁱⁱ are each independently H, C _{1 -6} - alkyl, C _{1 -6} - alkyl, ^{-NR iii R iv, - (CO} ) OC 1 -6 - alkyl, -C (O) -NR ⁱⁱⁱ R _{^{iv, -C (O) -C 1}} -6 - _{alkyl, -S (O) 2 -C 1} -6 - alkyl, or ^{_{-S (O) 2 -NR iii R}} iv , and;

R ⁱⁱⁱ and R ^iv are each independently H or C _{1 -6} - alkyl;

m is 1 to 6;

n is 0-4, or a pharmaceutically acceptable salt thereof.

More preferred are compounds of formula Ib according to any one of the embodiments described above, wherein R ² is one or two halogen atom (s).

Preference is furthermore given to compounds of the formula (lb) according to any one of the embodiments described above, wherein R ² is a halogen atom at position 6 of the indole. Preferably, the halogen atom at position 6 of the indole is Cl.

In one R ² is 5 times of the indole position C _{1 - 6} alkyl or a halogen atom, one of R ² is a halogen atom at the 6-position of the indole of formula according to any one of the embodiments as described above Ib The compound of is more preferable. Preferably, R ² at position 5 of the indole is F or Me, and R ² at position 6 of the indole is Cl.

R ³ is C _{1 -6} - The compounds of formula (Ib) according to any one of the alkyl, the above-described embodiment is more preferable.

R ³ is C _{1 -6} - is alkyl, and R ² is H the compounds of formula (Ib) according to any one of the embodiments as described above is more preferable.

R ³ is C _{1 -6} - alkyl and R ² is H or R ³ is H and R ² is the formula according to any one of the halogen, particularly Cl in the 6-position of the indole, embodiments as described above Ib The compound of is more preferable.

The present invention includes, for example, the following compounds:

(1-benzyl-2-methyl-1H-indol-3-yl)-(1,4-dioxa-8-aza-spiro [4.5] dec-8-yl) -methanone; And

8-[(6-chloro-1H-indol-3-yl) carbonyl] -1,4-dioxa-8-azaspiro [4.5] decane.

The invention also includes compounds of formula (I), (I-a) or (I-b) for use in the prevention or treatment of dysmenorrhea, hypertension, chronic heart failure, inappropriate secretion of vasopressin, cirrhosis, kidney syndrome, obsessive compulsive disorder, anxiety and depressive disorders.

The invention also includes a pharmaceutical composition comprising a compound of Formula (I), (I-a) or (I-b), useful for dysmenorrhea, hypertension, chronic heart failure, inappropriate secretion of vasopressin, cirrhosis, kidney syndrome, obsessive-compulsive disorder, anxiety and depressive disorder.

The present invention also encompasses the use of Formula I, I-a or I-b compounds for the preparation of medicaments useful for dysmenorrhea, hypertension, chronic heart failure, inappropriate secretion of vasopressin, cirrhosis, kidney syndrome, obsessive compulsive disorder, anxiety and depressive disorders.

The present invention also includes methods of preparing compounds of Formula (I), (I-a) or (I-b).

In some embodiments, a compound of formula (I) of the present invention may be prepared according to a method comprising the step of reacting a compound of formula (II) with a compound of formula (A-H) to obtain a compound of formula (I):

Where

R ¹ , R ² , R ³ and A are as defined above for Formula (I).

The synthesis is optionally carried out in an inert solvent.

Amide couplings themselves are known to those skilled in the art. Optionally, carboxylic acid II is activated in the first step or in situ during the amide synthesis. Activated species of carboxylic acid II are, for example, acid chlorides, anhydrides or mixed anhydrides, azides or activated esters. Examples of activated esters are pentachloro- or pentafluorophenol esters of carboxylic acid II. Activating reagents for activation of the carboxylic acid during amide synthesis are, for example, carbodiimides which form activated esters as intermediates, ie each O-acyl-urea. Examples of carbodiimide are N, N'-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) or N, N'-dia Isopropylcarbodiimide (DIC), each of which is a coupling reagent such as N-hydroxybenzotriazole (HOBt), O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU), 4-dimethylaminopyridine (DMAP) and the like may optionally be combined. Further activation reagent is N, N'-carbonyl-di-imidazole, which forms each acid imidazoleide as an activated intermediate.

The method is described in more detail in the following general scheme and procedure A.

In another embodiment, a compound of formula (I) of the present invention may be prepared according to a process comprising the step of reacting a compound of formula (I1) with a compound of formula (R ¹ -X) to obtain a compound of formula (I):

Where

X is halo, preferably Cl,

R ¹ and R ⁴ are as defined above for Formula I, but not H,

R ² and R ³ are as defined above for Formula (I).

The method is described in more detail in the following general scheme and procedure B.

In yet another embodiment, a compound of formula (Ia) of the present invention may be prepared according to a method comprising the step of reacting a compound of formula (Ia1) with a compound of formula (R ⁴ -X) to obtain a compound of formula (Ia) :

Where

X is halo, preferably Cl,

R ¹ , R ⁴ and R ⁵ are as defined above for Formula I, but not H,

R ² and R ³ are as defined above for Formula (I).

The method is described in more detail in the following general scheme and procedure C.

As already mentioned above, the aforementioned methods are described in more detail in the following general schemes and processes A to C. General scheme and process D show how to prepare useful intermediates of formula (II).

General Scheme A

Compounds of formula (I) can be prepared via amide coupling between indole 3-carboxylic acid (II) and piperidine (A-H). Indole 3-carboxylic acid (II) is commercially available or described in J. Med. Chem. 1991, 34, 140 can be easily prepared using the procedure disclosed in the following or according to the general scheme D below. Piperidine derivatives A-H are either commercially available or prepared using published procedures.

General Scheme B

Compounds of formula (I-2) (compounds of formula (I) in which both R ¹ and R ⁴ are not H) are prepared using standard procedures, indole derivatives of formula (I1) (compounds of formula (I) wherein R ¹ is H and R ⁴ ) May be prepared by alkylation with an electrophile of formula R ¹ -X (commercially available, wherein X is halo, preferably Cl or Br). Derivative I-1 is prepared using the method described in general Scheme A.

General Scheme C

Compounds of formula (Ia2) (compounds of formula (I) in which both R ¹ and R ⁴ are not H) and derivative I-a1 (compounds of formula (Ia) wherein R ⁴ is H and R ¹ is not H) using standard procedures It can be prepared by alkylation with an electrophile of R ⁴ -X (commercially available, wherein X is halo, preferably Cl or Br). Derivatives I-a1 are prepared using the methods described in Scheme A in general.

General Scheme D

The indole derivative of formula III was treated with trifluoroacetic anhydride in DMF to prepare the intermediate of formula IV and then hydrolyzed with aqueous sodium hydroxide solution to prepare the 3-carboxylic acid indole derivative of formula II-a. On the other hand, the compound of formula IV is reacted with an electrophile of formula R ¹ -X (commercially available, wherein X is halo, preferably Cl or Br and R ¹ is not H) And then convert it to the corresponding carboxylic acid derivative of formula II-b using NaH / H ₂ O in DMF (J. Org Chem., 1993, 10, 2862).

Result-V1a Activity

Substance & Method:

Human Vla receptors were cloned by RT-PCR from whole human liver RNA. The coding sequence was subcloned into the expression vector and then sequenced to confirm the identity of the amplified sequence. Binding studies were performed to demonstrate the affinity of the compounds of formula (I) of the invention for human Vla receptors. Cell membranes were prepared from HEK293 cells transiently transfected with the expression vector and propagated in a 20 liter fermentor using the following protocol.

Cells 50 g of a newly prepared ice-cold lysis buffer (50 mM HEPES, 1 mM EDTA , complete cocktail (Roche Diagnostics) in a 10 mM MgCl ₂ + protease inhibitors adjusted to pH 7.4) and resuspended in 30 ㎖. Homogenize with polytron for 1 min and sonicate at 80% intensity for 2 x 2 min on ice (Vibracell sonicator). The formulation is centrifuged at 500 g for 20 min at 4 ° C, the pellet is discarded and the supernatant is centrifuged at 43,000 g (19,000 rpm) for 1 hour at 4 ° C. The pellet is resuspended in 12.5 ml of lysis buffer + 12.5 ml of 20% sucrose and homogenized for 1 to 2 minutes using polytron. Protein concentration is measured by the Bradford method and aliquots are stored at -80 ° C until use. For binding studies, 60 mg of yttrium silicate SPA beads (Amersham) are mixed with membrane aliquots while mixing in binding buffer (50 mM Tris, 120 mM NaCl, 5 mM KCl, 2 mM CaCl ₂ , 10 mM MgCl ₂ ) for 15 minutes. . 500 ul of bead / membrane mixture is then added to each well of a 96 well plate followed by 50 ul of 4 nM 3H-Vaspressin (American radiolabeled Chemicals). 100 ul of binding buffer is added to each well for total binding measurement, 100 ul of 8.4 mM cold vasopressin for non-specific binding, and 100 ul of serial dilutions of each compound in 2% DMSO for compound testing. The plates are incubated for 1 hour at room temperature, centrifuged at 1000 g for 1 minute and counted on Packard Top-Count. Non specific binding counts are subtracted from each well and data normalized to 100% maximum specific binding. To calculate the IC ₅₀ the curve is substituted using a nonlinear regression model (XLfit) and Ki is calculated using the Cheng-Prussoff equation.

Example Compound Ki (nM) Example Compound Ki (nM) One 368 11 45 2 367 13 73 7 156 14 184 8 37 15 424 9 21 16 284 10 14

The compounds of formula (I), (I-a) or (I-b) as well as pharmaceutically usable acid addition salts thereof can be used as medicaments, for example in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. However, the administration can also be carried out by rectum, for example in the form of suppositories, or orally, for example in the form of injections.

The compounds of formula (I), (I-a) or (I-b) and their pharmaceutically acceptable acid addition salts can be processed using pharmaceutically inert, inorganic or organic excipients for the preparation of tablets, coated tablets, dragees and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as excipients for tablets, dragees and hard gelatin capsules.

Suitable excipients for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols and the like.

Suitable excipients for the preparation of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose and the like.

Suitable excipients for injectable solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils and the like.

Suitable suppository excipients are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

Moreover, the pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavors, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. It may also still contain other therapeutically valuable substances.

Dosages can be varied within wide limits and will, of course, be tailored to the individual requirements in each particular case. In general, for oral administration, a daily dosage of about 10 to 1000 mg of Formula (I), (I-a) or (I-b) compound per person will be suitable, but may be above the upper limit as necessary.

The following examples illustrate the invention without limitation. All temperatures are in degrees Celsius.

Example  A

Tablets of the following composition are prepared in a conventional manner:

Mg / tablet Active substance 5 Lactose 45 Corn starch 15 Microcrystalline cellulose 34 Magnesium stearate One Tablet weight 100

Example  B

A capsule of the following composition is prepared:

Mg / capsules Active substance 10 Lactose 155 Corn starch 30 talc 5 Capsule Fill Weight 200

The active substance, lactose and corn starch are first mixed in a mixer and then in a grinder. The mixture is returned to the mixer, talc is added to it and mixed thoroughly. The mixture is mechanically filled into hard gelatin capsules.

Example  C

Suppositories of the following compositions are prepared:

Mg / suppositories Active substance 15 Suppository mass 1285 All 1300

The suppository mass is melted in a glass or steel container, mixed thoroughly and cooled to 45 ° C. Immediately thereafter, the finely divided active substance is added to it and stirred until it is completely dispersed. The mixture is poured into suppository molds of suitable size and cooled; The suppository is then removed from the mold and individually filled in wax paper or metal foil.

Example

When journal references were cited in the examples, the examples were performed using the starting materials listed with the reactants and conditions cited in the references. All of the procedures in such references are well known to those of ordinary skill in the art. All journal references cited in the present invention are incorporated by reference.

General Process I-Amide Coupling:

To a stirred solution of type II indole-3-carboxylic acid derivative (1 mmol) in 10 mL of CH ₂ Cl ₂ , EDC (1.3 mmol), HOBt (1.3 mmol), Et ₃ N (1.3 mmol) and amine derivative (AH) ( 1 mmol) was added. The mixture was stirred at rt overnight, then poured into water and extracted with CH ₂ Cl ₂ . The combined organic phases were dried over Na ₂ SO ₄ and concentrated in vacuo. Flash chromatography or preparative HPLC gave the compound of formula (I).

General Process II-Alkylation:

2.1 equivalents of NaH (60% in oil) was added to a stirred solution of the formula I1 derivative in DMF. The mixture was stirred at rt for 30 min and then electrophilic reactant R ¹ -X (1.1 equiv) was added. The mixture was stirred for an additional 14 hours at 60 ° C. and then poured into water and extracted with ethyl acetate. The combined organic phases were dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by preparative HPLC gave the corresponding derivative of formula I-2.

Chemical formula II Acid intermediates

Mountain 1

1-benzyl-2-methyl-1H-indole-3-carboxylic acid

0.27 g (6.75 mmol) of NaH (60% in oil) in a stirred solution of 2-methyl-1H-indole-3-carboxylic acid (disclosed in J. Heterocyclic Chem. 1977, 14, 1123) in 5 ml of DMF. ) Was added. The mixture was stirred at rt for 30 min and then 0.39 mL (3.28 mmol) benzyl bromide was added. The mixture was stirred for an additional hour, then poured into water and extracted with ethyl acetate. The combined organic phases were dried over Na ₂ SO ₄ and concentrated in vacuo. Crystallization from Et ₂ O gave 1-benzyl-2-methyl-1H-indole-3-carboxylic acid.

Mountains 2

6-chloro-1H-indole-3-carboxylic acid

a) 1- (6- Chloro -1H-indol-3-yl) -2,2,2- Trifluoro - Ethanon

To a solution of 15.0 g (98.9 mmol) of 6-chloroindole in 150 mL of anhydrous N, N-dimethylformamide was added dropwise 15.8 mL (114 mmol) of trifluoroacetic anhydride at 0 ° C. under argon. After stirring for 2 hours at 0 ° C., another aliquot of 15.8 mL (114 mmol) of trifluoroacetic anhydride was added and stirring was continued for 30 minutes. It was quenched with saturated aqueous sodium carbonate solution and then extracted with three aliquots of ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was triturated with tertiary butyl methyl ether. Filtration gave 20.4 g (82%) of the title compound as a white solid. The mother liquor was concentrated in vacuo and triturated with tert butyl methyl ether to give another aliquot of 1.2 g (5%) of the title compound.

MS m / e (%): 246 (MH ⁺ , 100)

b) 6- Chloro -1H-indole-3- Carboxylic acid

A 21.6 g (87.2 mmol) solution of 1- (6-chloro-lH-indol-3-yl) -2,2,2-trifluoro-ethanone in 110 ml of potassium hydroxide 4M aqueous solution was heated to reflux for 2 hours. After cooling to 0 ° C., white solid was precipitated from the solution by neutralization with 36.7 mL of concentrated aqueous hydrochloric acid solution. The solid was collected by filtration and washed with water. Drying under high vacuum at 80 ° C. yielded 16.4 g (96%) of the title compound as a light yellow solid.

MS m / e (%): 194 (MH ⁺ , 100)

Examples of Compounds of Formula Ia

Example  One

8-[(1-benzyl-2-methyl-1H-indol-3-yl) carbonyl] -3-methyl-1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one

Amide coupling according to general procedure I:

-Amine: 3-methyl-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one (disclosed in App. Radiat. Isot. 1995, 46, 911);

-Acid: 1-benzyl-2-methyl-1H-indole-3-carboxylic acid;

ES-MS m / e (%): 493.5 (M + H ⁺ ).

Example  2

8- (1-benzyl-2-methyl-1H-indole-3-carbonyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one

Amide coupling according to general procedure I:

-Amines: 1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one (commercially available);

-Acid: 1-benzyl-2-methyl-1H-indole-3-carboxylic acid;

E-MS m / e (%): 479.4 (M + H ⁺ ).

Example  3

8- (1-benzyl-2-methyl-1H-indole-3-carbonyl) -1- (4-chloro-phenyl) -1,3,8-triaza-spiro [4.5] decan-4-one

Amide coupling according to general procedure I:

Amines: 1- (4-chloro-phenyl) -1,3,8-triaza-spiro [4.5] decan-4-one (disclosed in WO 2005040166 A1);

-Acid: 1-benzyl-2-methyl-1H-indole-3-carboxylic acid;

ES-MS m / e (%): 513.1 (M + H ⁺ ).

Example  4

8- (6-Chloro-1H-indole-3-carbonyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one

Amide coupling according to general procedure I:

-Amines: 1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one (commercially available);

-Acid: 6-chloro-lH-indole-3-carboxylic acid;

ES-MS m / e (%): 409 (M + H ⁺ ).

Example  5

8- (1H-indole-3-carbonyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one

Amide coupling according to general procedure I:

-Amines: 1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one (commercially available);

-Acid: 1H-indole-3-carboxylic acid (commercially available);

ES-MS m / e (%): 375.3 (M + H ⁺ ).

Example  6

8-[(6-chloro-1H-indol-3-yl) carbonyl] -3-methyl-1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one

According to general procedure I, 3-methyl-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one (disclosed in App. Radiat. Isot. 1995, 46, 911) ) Is coupled with 6-chloro-1H-indole-3-carboxylic acid to afford the title compound.

ES-MS m / e (%): 423.5 (M + H ⁺ ).

Example  7

8-({6-chloro-1- [2- (dimethylamino) ethyl] -1H-indol-3-yl} carbonyl) -3-methyl-1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one

8-[(6-chloro-1H-indol-3-yl) carbonyl] -3-methyl-1-phenyl-1,3,8-triazaspiro [4.5] decane-4-, according to general procedure II. One was coupled with (commercially available) (2-chloro-ethyl) -dimethyl-amine to afford the title compound.

ES-MS m / e (%): 494.2 (M + H ⁺ ).

Example  8

2- {6-chloro-3-[(3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro [4.5] dec-8-yl) carbonyl] -1H-indole-1 -Yl} -N-methylacetamide

8-[(6-chloro-1H-indol-3-yl) carbonyl] -3-methyl-1-phenyl-1,3,8-triazaspiro [4.5] decane-4-, according to general procedure II. One was coupled with (commercially available) 2-chloro-N-methyl-acetamide to afford the title compound.

ES-MS m / e (%): 494.2 (M + H ⁺ ).

Example  9

8-{[6-chloro-1- (3,5-difluorobenzyl) -1H-indol-3-yl] carbonyl} -3-methyl-1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one

8-[(6-chloro-1H-indol-3-yl) carbonyl] -3-methyl-1-phenyl-1,3,8-triazaspiro [4.5] decane-4-, according to general procedure II. One was coupled with (commercially available) 1-chloromethyl-3,5-difluoro-benzene to afford the title compound.

ES-MS m / e (%): 549.2 (M + H ⁺ ).

Example  10

2- {6-chloro-3-[(3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro [4.5] dec-8-yl) carbonyl] -1H-indole-1 -Yl} -N, N-dimethylacetamide

8-[(6-chloro-1H-indol-3-yl) carbonyl] -3-methyl-1-phenyl-1,3,8-triazaspiro [4.5] decane-4-, according to general procedure II. One was coupled with 2-chloro-N, N-dimethyl-acetamide (commercially available) to afford the title compound.

ES-MS m / e (%): 508.2 (M + H ⁺ ).

Example  11

8-[(1-benzyl-6-chloro-1H-indol-3-yl) carbonyl] -3-methyl-1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one

8-[(6-chloro-1H-indol-3-yl) carbonyl] -3-methyl-1-phenyl-1,3,8-triazaspiro [4.5] decane-4-, according to general procedure II. One was coupled with benzyl chloride (commercially available) to afford the title compound.

ES-MS m / e (%): 513.2 (M + H ⁺ ).

Example  12

2- {6-chloro-3-[(3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro [4.5] dec-8-yl) carbonyl] -1H-indole-1 Acylamide

8-[(6-chloro-1H-indol-3-yl) carbonyl] -3-methyl-1-phenyl-1,3,8-triazaspiro [4.5] decane-4-, according to general procedure II. One was coupled with 2-chloro-acetamide (commercially available) to afford the title compound.

ES-MS m / e (%): 480.2 (M + H ⁺ ).

Example  13

8-{[6-chloro-1- (3-chloro-2-fluorobenzyl) -1H-indol-3-yl] carbonyl} -3-methyl-1-phenyl-1,3,8-triaza Spiro [4.5] decan-4-one

8-[(6-chloro-1H-indol-3-yl) carbonyl] -3-methyl-1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one following the usual procedure Was coupled with (commercially available) 1-chloro-3-chloromethyl-2-fluoro-benzene to afford the title compound.

ES-MS m / e (%): 565.2 (M + H ⁺ ).

Example  14

2- {6-chloro-3-[(3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro [4.5] dec-8-yl) carbonyl] -1H-indole-1 -Yl} -N- [2- (dimethylamino) ethyl] acetamide

a) [6- Chloro -3- (3- methyl -4-oxo-1- Phenyl -1,3,8- Triaza - Spiro [4.5] Decan -8- Carbonyl ) -Indol-1-yl] -acetic acid

8-[(6-chloro-1H-indol-3-yl) carbonyl] -3-methyl-1-phenyl-1,3,8-triazaspiro [4.5] decane-4-, according to general procedure II. One was coupled with bromo-acetic acid (commercially available) to afford the title compound.

ES-MS m / e (%): 479.1 (M−H ⁺ ).

b) 2- {6- Chloro -3-[(3- methyl -4-oxo-1- Phenyl -1,3,8- Triaza Spiro [4.5] deck -8- days) Carbonyl ] -1H-indol-1-yl} -N- [2- ( Dimethylamino )ethyl] Acetamide

[6-Chloro-3- (3-methyl-4-oxo-phenyl-1,3,8-triaza-spiro [4.5] decane-8-carbonyl) -indol-1-yl] -acetic acid solution in DMF 1 equivalent of O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate, 1 equivalent of N, N-diisopropylethylamine And 1 equivalent of N, N-dimethylethylenediamine. The mixture was shaken for 12 h at room temperature, concentrated and purified by preparative HPLC to afford the title compound.

ES-MS m / e (%): 551.2 (M + H ⁺ ).

Examples of Compounds of Formula Ib

Example  15

(1-benzyl-2-methyl-1H-indol-3-yl)-(1,4-dioxa-8-aza-spiro [4.5] dec-8-yl) -methanone

Amide coupling according to general procedure I:

-Amines: 1,4-dioxa-8-aza-spiro [4.5] decane (commercially available);

-Acid: 1-benzyl-2-methyl-1H-indole-3-carboxylic acid;

ES-MS m / e (%): 391.5 (M + H ⁺ ).

Example  16

8-[(6-chloro-1H-indol-3-yl) carbonyl] -1,4-dioxa-8-azaspiro [4.5] decane

Amide coupling according to general procedure I:

-Amines: 1,4-dioxa-8-aza-spiro [4.5] decane (commercially available);

-Acid: 6-chloro-lH-indole-3-carboxylic acid.

Claims (24)

A compound of formula (I) or a pharmaceutically acceptable salt thereof: Formula I

Where R ¹ is H; C _{1 -6} - alkyl; Aryl, 5- or 6-membered heteroaryl or sulfonylaryl, each optionally substituted by one or more B; ^{_{- (CH 2) m -R a}} ( where R ^a is CN, OR ^i, NR ⁱ R ^ii, each of which is optionally substituted C _{3 -6} by one or more B in -cycloalkyl, 4 to 7 heterocycloalkyl won Alkyl, aryl, or 5 or 6 membered heteroaryl); _{- (CH 2) n - (} CO) -R b or _{- (CH 2) n - (} SO 2) -R b ( where R ^b is C _{1 -6} - alkyl, C _{1 -6} - alkoxy, C _{3 -6} -cycloalkyl,-(CH ₂ ) _m -NR ⁱⁱⁱ R ^iv , NR ⁱ R ^ii, respectively, it is optionally substituted by one or more B A C _{3 -6} - a cycloalkyl, 4 to 7 membered heterocycloalkyl of, aryl, or 5 or 6 membered heteroaryl), or; Or R ¹ and R ³ together with the indole ring to which they are attached form a 5 or 6 membered heterocycloalkyl optionally substituted by = O; At least one R ² is present, wherein each R ² is the same or different, R ² is H; OH; Halo; CN; Nitro; -NR ⁱⁱⁱ R ^iv, optionally substituted C _{1 -6} by -alkyl; C _{1 -6} - alkoxy; -O-CH ₂ -C _{2 -6} - alkenyl; Or benzyloxy; Or two R ² together with the indole ring to which they are attached form an oxo or dioxo bridge; R ³ is H; Halo; - (CO) -R ^c (where R ^c is C _{1 -6} - _{alkyl, - (CH 2) n -NR} i R ii, - (CH 2) n -NR iii R iv, or C _{1 -6} - 5 or 6 membered heterocycloalkyl optionally substituted by alkyl); Or each is _{halo, -O (CO) -C 1 -6} - alkyl or -NH (CO) R ^d (where R ^d is an optionally substituted C _{1 -6} by a halo or nitro-alkyl, or R ^d are each a halo, nitro, C _{1 -6} - alkyl or C _{1 -6} - halo-alkyl optionally substituted by aryl or 5 or by a 6-membered heteroaryl), optionally substituted C _{1 -6} - alkyl Or aryl; B is halo; CN; NR ⁱ R ⁱⁱ ; CN, halo or C _{1 -6} - alkoxy optionally substituted by C _{1 -6} - alkyl; C _1-6 -alkoxy; C _{1 -6} - haloalkoxy; C _{3 -6} - cycloalkyl; -C (O) OC _{1 -6} - alkyl; -C (O) NR ⁱ R ⁱⁱ ; -C (O) -C _1-6 -alkyl; _{-S (O) 2 -C 1 -6} - alkyl; -S (O) ₂ -NR ⁱ R ⁱⁱ ; Or (CR ⁱⁱⁱ R ^iv ) _n -phenyl, or (CR ⁱⁱⁱ R ^iv ) _n -5 or 6 membered heteroaryl, wherein the phenyl or 5 or 6 membered heteroaryl moiety is halo, CN, NR ⁱ R ^ii, CN or C _{1 -6} - alkoxy optionally substituted by C _{1 -6} - alkyl, C _{1 -6} - alkoxy, C _{1 -6} - haloalkoxy, C _{3 -6} - cycloalkyl, -C (O) OC _{1 -6} - ^{alkyl, -C (O) -NR i R} ii, -C (O) -C 1 -6 - _{alkyl, -S (O) 2 -C 1} -6 - alkyl, and -S (O) Optionally substituted by one or more substituent (s) selected from the group consisting of ₂ -NR ⁱ R ⁱⁱ ); R ⁱ and R ⁱⁱ are each independently H, C _{1 -6} - alkyl, C _{1 -6} - alkyl, ^{-NR iii R iv, - (CO} ) OC 1 -6 - alkyl, -C (O) -NR ⁱⁱⁱ R _{^{iv, -C (O) -C 1}} -6 - _{alkyl, -S (O) 2 -C 1} -6 - alkyl, or ^{_{-S (O) 2 -NR iii R}} iv , and; R ⁱⁱⁱ and R ^iv are each independently H or C _{1 -6} - alkyl; m is 1 to 6; n is 0 to 4; A is a group of formula a or b: Formula a

Formula b

(Wherein R ⁴ is H or C _{1 -6} - alkyl; R ⁵ is aryl optionally substituted by halo). The method of claim 1, A is a group (b) and R ¹ = R ² = R ³ = H; And A is a group (b) and R ² = OH, C _{1 -6} in the 5-position of the indole-alkoxy or benzyloxy a compound except the compound or a pharmaceutically acceptable salt thereof of formula I. The method of claim 1, A compound of formula la: Formula Ia

Where R ¹ to R ⁵ are as defined in claim 1. The method of claim 3, wherein R ¹ is H; C _{1 -6} - alkyl; Aryl, 5- or 6-membered heteroaryl, sulfonylaryl, each optionally substituted by one or more B; ^{_{- (CH 2) m -R a}} ( where R ^a is CN, NR ⁱ R ^ii, each of which is optionally substituted by one or more C _{3 -6} B - cycloalkyl, 4 to 7 membered heterocycloalkyl of aryl Or 5 or 6 membered heteroaryl; _{- (CH 2) n - (} CO) -R b or _{- (CH 2) n - (} SO 2) R b -R ^b in (W groups are C _{1 -6} - alkoxy, NR ⁱ R ^ii, each one 4 to 7 membered heterocycloalkyl, aryl, or 5 or 6 membered heteroaryl optionally substituted by B or more); Or R ¹ and R ³ together with the indole ring to which they are attached form a 5 or 6 membered heterocycloalkyl optionally substituted by = O; At least one R ² is present, wherein each R ² is the same or different, R ² is H; OH; Halo; -NR ⁱⁱⁱ R ^iv, optionally substituted C _{1 -6} by -alkyl; Or C _{1 -6} - represents at least one alkoxy group; R ³ is H; - (CO) -R ^c (where R ^c is ^{_{- (CH 2) n -NR i}} R ii, - (CH 2) n -NR iii R iv, C 1 -6 - alkyl optionally substituted by a 5 or 6 membered heterocycloalkyl); Or each of which is optionally substituted by a halo-C _{1 -6} - alkyl or aryl; B is halo; NH ₂ ; CN or a C _{1 -6-alkoxy} optionally substituted by C _{1 -6} -alkyl; C _{1 -6} - alkoxy; C _1-6 -haloalkoxy; C _{3 -6} - cycloalkyl; -C (O) OC _{1 -6} - alkyl; - (CR ⁱⁱⁱ R ^iv) _n -, and phenyl (wherein phenyl is halo, by CN or halo, optionally substituted C _{1 -6} - alkyl and C _{1 -6} - substituent at least one selected from the group consisting of alkoxy group (s) Optionally substituted); R ⁱ and R ⁱⁱ are each independently H, C _{1 -6} - alkyl, C _{1 -6} - alkyl, ^{-NR iii R iv, - (CO} ) OC 1 -6 - alkyl, -C (O) -NR ⁱⁱⁱ R _{^{iv, -C (O) -C 1}} -6 - _{alkyl, -S (O) 2 -C 1} -6 - alkyl, or ^{_{-S (O) 2 -NR iii R}} iv , and; R ⁱⁱⁱ and R ^iv are each independently H or C _{1 -6} - alkyl; m is 1 to 6; n is 0 to 4; R ⁴ is H or C _{1 -6} - alkyl; R ⁵ is aryl optionally substituted by halo, A compound of formula (Ia) or a pharmaceutically acceptable salt thereof. The method of claim 3, wherein R ¹ is H; C _{1 -6} - alkyl; Phenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, sulfonylphenyl, each optionally substituted by one or more B; ^{_{- (CH 2) m -R a}} ( where R ^a is CN, NR ⁱ R ^ii, each of which is optionally substituted by one or more B C _{3 -6} - cycloalkyl, oxetanyl, piperazinyl, tetrahydro Pyranyl, morpholinyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, pyrazolyl or imidazolyl); -(CH ₂ ) _n- (CO) -R ^b or-(CH ₂ ) _n- (SO ₂ ) -R ^b , where R ^b is C _{1 -6} - alkoxy, NR ⁱ R ^ii, each of which is optionally an oxetanyl substituted by one or more B, piperidinyl, piperazinyl, morpholinyl or phenyl, a carbonyl), or; Or R ¹ and R ³ together with the indole ring to which they are attached form a 5 or 6 membered heterocycloalkyl which may be substituted by (CO); At least one R ² is present, wherein each R ² is the same or different, R ² is H, OH, Cl, Br, -NR iii R iv on optionally substituted by C _{1 -6-alkyl,} OMe, or OEt, and one or more of; R ³ is H; - (CO) -R ^c (where R ^c is ^{_{- (CH 2) n -NR i}} R ii, - (CH 2) n -NR iii R iv, respectively, are C _{1 -6} - alkyl optionally substituted by a Oxetanyl, piperidinyl, piperazinyl or morpholinyl); Or each of which is optionally substituted by Cl C _{1 -6} - alkyl or aryl; B is halo; NH ₂ ; CN or a C _{1 -6-alkoxy} optionally substituted by C _{1 -6} -alkyl; C _{1 -6} - alkoxy; C _1-6 -haloalkoxy; C _{3 -6} - cycloalkyl; -C (O) OC _{1 -6} - alkyl; Or _{^{- (CR iii R iv) n}} - , and phenyl (wherein phenyl is halo, by CN or halo, optionally substituted C _{1 -6} - alkyl and C _{1 -6} - substituent at least one selected from the group consisting of alkoxy (the Optionally substituted); R ⁱ and R ⁱⁱ are each independently H, C _{1 -6} - alkyl, C _{1 -6} - alkyl, ^{-NR iii R iv, - (CO} ) OC 1 -6 - alkyl, -C (O) -NR ⁱⁱⁱ R _{^{iv, -C (O) -C 1}} -6 - _{alkyl, -S (O) 2 -C 1} -6 - alkyl, or ^{_{-S (O) 2 -NR iii R}} iv , and; R ⁱⁱⁱ and R ^iv are each independently H or C _{1 -6} - alkyl; m is 1 to 6; n is 0 to 4; R ⁴ is H or C _{1 -6} - alkyl; R ⁵ is aryl optionally substituted by halo, A compound of formula (Ia) or a pharmaceutically acceptable salt thereof. The method according to any one of claims 3 to 5, A compound of formula la wherein R ² is one or two halogen atom (s). The method according to any one of claims 3 to 6, A compound of formula la wherein R ² is a halogen atom at position 6 of the indole. The method according to any one of claims 3 to 7, A compound of formula Ia wherein R ² is Cl at position 6 of the indole. The method according to any one of claims 3 to 5, In one R ² is 5 times of the indole position C _{1 - 6} alkyl or a halogen atom, one of R ² is a halogen atom at the 6-position of the indole compound of formula Ia. The method of claim 3, wherein A compound of formula (Ia) selected from the group consisting of: 2- [6-Chloro-3- (3-methyl-4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] decane-8-carbonyl) -indol-1-yl]- N, N-dimethyl-acetamide; 8- [6-Chloro-1- (3,5-difluoro-benzyl) -1H-indole-3-carbonyl] -3-methyl-1-phenyl-1,3,8-triaza-spiro [ 4.5] decan-4-one; 2- [6-Chloro-3- (3-methyl-4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] decane-8-carbonyl) -indol-1-yl]- N-methyl-acetamide; 8- (1-benzyl-6-chloro-1H-indole-3-carbonyl) -3-methyl-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one; 8- [6-Chloro-1- (3-chloro-2-fluoro-benzyl) -1H-indole-3-carbonyl] -3-methyl-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one; 8- [6-chloro-1- (2-dimethylamino-ethyl) -1H-indole-3-carbonyl] -3-methyl-1-phenyl-1,3,8-triaza-spiro [4.5] Decan-4-one; 2- [6-Chloro-3- (3-methyl-4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] decane-8-carbonyl) -indol-1-yl]- N- (2-dimethylamino-ethyl) -acetamide; 8- (1-benzyl-2-methyl-1H-indol-3-carbonyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one; 8-[(1-benzyl-2-methyl-1H-indol-3-yl) carbonyl] -3-methyl-1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one ; 8- (6-chloro-1H-indol-3-carbonyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one; 2- [6-Chloro-3- (3-methyl-4-oxo-1-phenyl-1,3,8-triaza-spiro [4.5] decane-8-carbonyl) -indol-1-yl]- Acetamide; 8- (1-benzyl-2-methyl-1H-indole-3-carbonyl) -1- (4-chloro-phenyl) -1,3,8-triaza-spiro [4.5] decan-4-one; 8- (1H-indole-3-carbonyl) -1-phenyl-1,3,8-triaza-spiro [4.5] decan-4-one; And 8-[(6-chloro-1H-indol-3-yl) carbonyl] -3-methyl-1-phenyl-1,3,8-triazaspiro [4.5] decan-4-one. The method of claim 1, A compound of formula (Ib) Formula Ib

Where R ¹ to R ³ are as defined in claim 1 or 2. The method of claim 11, R ¹ is H; C _{1 -6} - alkyl; Aryl, 5- or 6-membered heteroaryl or sulfonylaryl, each optionally substituted by one or more B; ^{_{- (CH 2) m -R a}} ( where R ^a is CN, NR ⁱ R ^ii, each of which is optionally substituted by one or more C _{3 -6} B - cycloalkyl, 4 to 7 membered heterocycloalkyl of aryl Or 5 or 6 membered heteroaryl; _{- (CH 2) n - (} CO) -R b or _{- (CH 2) n - (} SO 2) -R b ( where R ^b is C _{1 -6} - or more alkoxy, NR ⁱ R ^ii, each one 4 to 7 membered heterocycloalkyl optionally substituted by B); Or R ¹ and R ³ together with the indole ring to which they are attached form a 5 or 6 membered heterocycloalkyl optionally substituted by = O; At least one R ² is present, wherein each R ² is the same or different, R ² is H, halo, or -NR ⁱⁱⁱ R ^iv on optionally substituted by C _{1 -6-alkyl,} and one or more; R ³ is H; - (CO) -R ^c (where R ^c is ^{_{- (CH 2) n -NR i}} R ii, - (CH 2) n -NR iii R iv, C 1 -6 - alkyl optionally substituted by a 5 or 6 membered heterocycloalkyl); Or each of which is optionally substituted by a halo-C _{1 -6} - alkyl or aryl; B is halo; NH ₂ ; CN or a C _{1 -6-alkoxy} optionally substituted by C _{1 -6} -alkyl; C _{1 -6} - alkoxy; C _1-6 -haloalkoxy; C _{3 -6} - cycloalkyl; -C (O) OC _{1 -6} - alkyl; Or _{^{- (CR iii R iv) n}} - , and phenyl (wherein phenyl is halo, by CN or halo, optionally substituted C _{1 -6} - alkyl and C _{1 -6} - substituent at least one selected from the group consisting of alkoxy (the Optionally substituted); R ⁱ and R ⁱⁱ are each independently H, C _{1 -6} - alkyl, C _{1 -6} - alkyl, ^{-NR iii R iv, - (CO} ) OC 1 -6 - alkyl, -C (O) -NR ⁱⁱⁱ R _{^{iv, -C (O) -C 1}} -6 - _{alkyl, -S (O) 2 -C 1} -6 - alkyl, or ^{_{-S (O) 2 -NR iii R}} iv , and; R ⁱⁱⁱ and R ^iv are each independently H or C _{1 -6} - alkyl; m is 1 to 6; n is from 0 to 4, A compound of formula (Ib) or a pharmaceutically acceptable salt thereof. The method of claim 12, R ¹ is H; C _{1 -6} - alkyl; Phenyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, or sulfonylphenyl, each optionally substituted by one or more B; ^{_{- (CH 2) m -R a}} ( where R ^a is CN, NR ⁱ R ^ii, each of which is optionally substituted by one or more B C _{3 -6} - cycloalkyl, oxetanyl, piperazinyl, tetrahydro Pyranyl, morpholinyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, pyrazolyl or imidazolyl); _{- (CH 2) n - (} CO) -R b or _{- (CH 2) n - (} SO 2) -R b ( where R ^b is C _{1 -6} - or more alkoxy, NR ⁱ R ^ii, each one Oxetanyl, piperidinyl, piperazinyl, morpholinyl or phenyl optionally substituted by B); Or R ¹ and R ³ together with the indole ring to which they are attached form a 5 or 6 membered heterocycloalkyl optionally substituted by = O; At least one R ² is present, wherein each R ² is the same or different, R ² is H, Cl, Br, or -NR ⁱⁱⁱ R ^iv on optionally substituted by C _{1 -6-alkyl,} and one or more; R ³ is H; - (CO) -R ^c (where R ^c is ^{_{- (CH 2) n -NR i}} R ii, - (CH 2) n -NR iii R iv, respectively, or a C _{1 -6} - optionally substituted by alkyl Oxetanyl, piperidinyl, piperazinyl, or morpholinyl); Or each of which is optionally substituted by Cl C _{1 -6} - alkyl or aryl; B is halo; NH ₂ ; CN or a C _{1 -6-alkoxy} optionally substituted by C _{1 -6} -alkyl; C _{1 -6} - alkoxy; C _1-6 -haloalkoxy; C _{3 -6} - cycloalkyl; -C (O) OC _{1 -6} - alkyl; Or _{^{- (CR iii R iv) n}} - , and phenyl (wherein phenyl is halo, by CN or halo, optionally substituted C _{1 -6} - alkyl and C _{1 -6} - substituent at least one selected from the group consisting of alkoxy (the Optionally substituted); R ⁱ and R ⁱⁱ are each independently H, C _{1 -6} - alkyl, C _{1 -6} - alkyl, ^{-NR iii R iv, - (CO} ) OC 1 -6 - alkyl, -C (O) -NR ⁱⁱⁱ R _{^{iv, -C (O) -C 1}} -6 - _{alkyl, -S (O) 2 -C 1} -6 - alkyl, or ^{_{-S (O) 2 -NR iii R}} iv , and; R ⁱⁱⁱ and R ^iv are each independently H or C _{1 -6} - alkyl; m is 1 to 6; n is from 0 to 4, A compound of formula (Ib) or a pharmaceutically acceptable salt thereof. The method of claim 11, A compound of formula (Ib) selected from the group consisting of: (1-benzyl-2-methyl-1H-indol-3-yl)-(1,4-dioxa-8-aza-spiro [4.5] dec-8-yl) -methanone; And 8-[(6-chloro-1H-indol-3-yl) carbonyl] -1,4-dioxa-8-azaspiro [4.5] decane. A process for preparing a compound of formula (I) according to claim 1 comprising reacting a compound of formula (II) with a compound of formula (A-H) to obtain a compound of formula (I): Formula II

Where R ¹ , R ² , R ³ and A are as defined in claim 1. A process for preparing a compound of formula I according to claim 1 comprising reacting a compound of formula I1 with a compound of formula R ¹ -X to obtain a compound of formula I: Formula I1

Where X is halo; R ¹ and R ⁴ are as defined in claim 1, but not H; R ² and R ³ are as defined in claim 1. A process for preparing a compound of formula (Ia) according to claim 3 comprising reacting a compound of formula (Ia1) with a compound of formula (R ⁴ -X) to obtain a compound of formula (Ia): Formula Ia1

Where X is halo; R ¹ , R ⁴ and R ⁵ are as defined in claim 3, but not H; R ² and R ³ are as defined in claim 1. 18. A compound of formula (I), (Ia) or (Ib) obtainable by the process according to any one of claims 15 to 17. Formula I, Ia according to any one of claims 1 to 14 for use in the prevention or treatment of dysmenorrhea, hypertension, chronic heart failure, inappropriate secretion of vasopressin, cirrhosis, kidney syndrome, obsessive compulsive disorder, anxiety and depressive disorder. Or a compound of Ib. A pharmaceutical composition comprising a compound of formula (I), (la) or (lb) according to any one of claims 1 to 14. The method of claim 20, Pharmaceutical compositions useful for dysmenorrhea, hypertension, chronic heart failure, inadequate secretion of vasopressin, cirrhosis, kidney syndrome, obsessive compulsive disorder, anxiety and depressive disorders. Use of a compound of formula (I), (la) or (lb) according to any one of claims 1 to 14 for the manufacture of a medicament. The method of claim 22, Use of the agent for dysmenorrhea, hypertension, chronic heart failure, inappropriate secretion of vasopressin, cirrhosis, kidney syndrome, obsessive-compulsive disorder, anxiety and depressive disorder. Invention as described above.